Estrogen-Receptor Loss and ESR1 Mutation in Estrogen-Receptor-Positive Metastatic Breast Cancer and the Effect on Overall Survival

In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation of <i>ESR1</i>-the gene encoding the ER receptor-are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. Metastases were retrieved from our pathology files. <i>ESR1</i> hotspot mutations resulting in p.(D538G), p.(Y537S), and p.(L536H) were determined by means of pyrosequencing. Clinical data were retrieved from electronic medical records. A total of 136 metastases were available for analysis. ER loss was found in 23 metastases (17%). <i>ESR1</i> mutations were found in 18 metastases (13%), including p.(D538G) in 9, p.(Y537S) in 7, and p.(L536H) in 2. <i>ESR1</i> mutation and ER loss were mutually exclusive (<i>p</i> = 0.042), and <i>ESR1</i> mutation was associated with endocrine therapy (<i>p</i> = 0.002). <i>ESR1</i> mutation was found in two primary breast cancers. <i>ESR1</i> mutations are rare in primary breast cancer and develop in metastases during endocrine therapy. Furthermore, ER loss had a statistically significant negative effect on overall survival when compared to patients without ER loss, with a rate ratio of 3.21 (confidence interval 1.95-5.26). No such effect was observed for <i>ESR1</i> mutations, with a rate ratio of 1.15 (confidence interval 0.67-1.95). We conclude that ER loss and <i>ESR1</i> mutation together account for 30% of the resistance to endocrine therapy.